A. We have recently reported atrial natriuretic factor mRNA expression and immunoreactivity in tumor and tumor cell lines from small cell lung cancer patients with hyponatremia who did not produce arginine vasopressin. High pressure liquid chromoatography (HPLC) analyses of the tumor cell lines and tumors from patients with hyponatremia and mRNA expression of atrial natriuretic factor have revealed that intracellular and extracellular peptide appears to be the 28 amino acid form of atrial natriuretic peptide, the form that normally circulates in human plasma. These studies are the first to characterize the ectopic production of atrial natriuretic peptide in small cell lung cancer patients and may have identified the third factor (natriuretic factor) that has been hypothesized in the syndrome of inappropriate antidiuretic hormone (SIADH). The receptor for atrial natriuretic factor is also present on small cell lung cancer cells and the cells respond to exogenously added atrial natriuretic factor with an increase in intracellular cGMP, similar to the normal receptors on vascular smooth muscle cells. Therefore, there appear to be functional ANF receptors on the surface of small cell lung cancer cells. B. We reviewed the clinical course of 234 lung cancer patients. In contrast to none of the 123 non-small cell lung cancer (NSCLC) patients, 18 of 111 (16%) small cell lung cancer patients had hyponatremia. Ten of these 18 had tumor cell lines available and 8 expressed ANF mRNA, 8 expressed AVP mRNA, and 6 of 10 cell lines produced both ANF and AVP mRNA. All of the 10 cell lines produced ANF mRNA, AVP mRNA, or both. Studies of 10 tumor cell lines from the 93 SCLC patients without hyponatremia showed 9 produced ANF mRNA and one produced AVP mRNA. From these studies we have observed that all tumor cell lines studied from SCLC patients with hyponatremia produce ANF mRNA or AVP mRNA, or both. Atrial natriuretic peptide may be the previously hypothesized third factor and play an important role in the pathogenesis of hyponatremia in some patients with SIADH.